Preparation of 2-oxo steroids and novel derivatives thereof



United States Patent 0 PREPARATION OF 2-OXO STEROIDS AND NOVELDERIVATIVES THEREOF 3,415,816 Patented Dec. 10, 1968 "ice configurationwhich comprises heating a 2a-bromo-3-oxo- Robert L. Clarke, Bethlehem,N.Y., assignor to Sterling Drug Inc., New York, N.Y., a corporation ofDelaware No Drawing. Filed Mar. 12, 1963, Ser. No. 264,661 25 Claims.(Cl. 260239.5)

This invention relates to a process for the preparation of2-oxo-steroids, including the preparation of androstan- 17/3-ol-2-oneand its esters, to products formed by said process, and to productsprepared by further chemical conversions of androstan-l7B-ol-2-one whichpossess endocrinological and pharmacological properties, for ex-- ample,anabolic, estrogenic, anti-adrenal, anti-pituitary, and hypotensiveactivities.

The process of aspect of the invention relates to a method for preparing2-oxo-steroids having the A/B trans steroid having the A/B transconfiguration with at least about three molar equivalents of alower-alkylmercaptan, and hydrolyzing the-product in the presence ofdilute acid.

The reaction between the Za-bIOITlO steroid and loweralkylmercaptan ispreferably carried out in an inert solvent at a' temperature betweenabout 50* C. and 150 C.

A preferred aspect of the invention is concerned with a method forpreparing androstan-l7 8-ol-2-one comprising heating a member of thegroup consisting of 2abromoandrostan-17/3-ol-3-one and lower carboxylicacid esters thereof with at least about three molar equivalents of alower-alkylmercaptan, andhydrolyzing the product in the presence ofdilute acid.

The process is believed to take place according to the followingsequence of reactions, as illustrated by the preparation ofandrostan-17B-ol-2-one:

The intermediate III also reacts in the alternative fashion as follows:

By the alternative route, the intermediate III reacts with thelower-alkylmercaptan to give a 3-lower-alkyl- VIII In the above formulasR stands for a lower-alkyl group preferably having from one to about sixcarbon atoms and R stands for a member of the group consisting ofhydrogen and lower-carboxylic acyl. When R is lowercarboxylic acyl, theacyl radicals are preferably derived from carboxylic acids having fromone to about ten carbon atoms, conventionally employed in the steroidart, and having a molecular weight less than about 200. Representativeof the acyl radicals which are contemplated are lower-alkanoyl radicals,e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, caproyl,heptanoyl, octanoyl, trimethylacetyl, and the like;carboxy-lower-alkanoyl radicals, e.g., succinyl (fi-carboxypropionyl);cycloalkyl-lower-alkanoyl radicals, e.g., fi-cyclopentylpropionyl,B-cyclohexylpropionyl, and the like; monocarbocyclic aroyl radicals,e.g., benzoyl, p toluyl, p nitrobenzoyl, 3,4,5 trimethoxybenzoyl, andthe like; monocarbocyclic aryllower-alkanoyl or -alkenoyl radicals, suchas phenylacetyl, 13 phenylpropionyl, cinnamoyl, and the like; andmonocarbocyclic aryloxy-lower-alkanoyl radicals, such asp-chlorophenoxyacetyl, and the like.

Referring to the above flow sheets, the 2a-bromo-17floxyandrostan-3-oneI reacts with a lower-alkylmercaptan to give as the initial product a2-lower-alkylmercapto-17 8 oxyandrostan-3-one II. Further addition oflower-alkylmercaptan followed by elimination of water gives a 2,3-bis(lower alkylmercapto) 17 3 oxyandrostane III. Still further reactionof the lower-alkylmercaptan in the presence of acid results inelimination of di-lower-alkyl disulfide, RSSR, and formation of a2-lower-alkylmercapto-l7fi-oxy-2-androstene IV. The latter is readilyhydrolyzed under acidic conditions to give 17B-hydroxyandrostan-Z-one V.If esters of androstan-l7fi-ol-2-one are desired, they can be preparedby conventional esterification reactions as by heating with theappropriate acid halide or acid anhydride in py idine solution.

mercapto-l7fi-oxy-2-androstene VI which is hydrolyzed with acid to 17 3hydroxyandrostan 3 one VII. The 3-lower-alkylmercapto-17/8-oxy-2-androstene in the presence of excesslower-alkylmercaptan and acid catalyst forms a thioketal, 3,3bis(loweralkylmercapto)-17fi-oxyandrostane VIII.

Evidence for the above reaction mechanism is provided by the isolationof, or evidence of the presence of, intermediates II, III, IV and VIunder varying conditions, and by the fact that the reaction producesapproximately equal amounts of the Z-ketone V and the 3-ketone VII. The2-ketone and 3-ketone are readily separated by making use of the factthat the latter forms an insoluble bi sulfite addition product whereasthe former does not. The 3-ketone can then be brominated to produce thestarting material I or the preparation of additional 2-ketone.

A further aspects of the invention relates to loweralkylsulfonylcompounds corresponding to the compounds of formulas III, IV, VI andVIII, wherein the sulfide linkages are replaced by sulfonyl SO linkages.Said sulfonyl compounds are prepared by oxidizing thelower-alkylmercapto compounds with hydrogen peroxide or a peracid.Biological evaluation of the lower-alkylsulfonyl compounds has shownthem to have endocrinological activity, e.g., anti-adrenal andanti-pituitary activities.

Androstan-17fi-ol-2-one and its esters V are useful as intermediates inthe preparation of other new and useful compounds also Within thepurview of the invention.

A Grignard reaction between androstan-l7fi-ol-2-0ne and methylmagnesiumhalide produces 2a-methylandrostane-25,17B-di0l, which has estrogenicactivity.

Androstan-17fl-ol-2-one can be caused to react with ethyl formate in thepresence of a strong base, such as an alkali metal lower-alkoxide,hydride or amide, to give 3-hydroxymethyleneandrostan-l7fi-ol-2-one. Thelatter in turn reacts with a secondary amine, B NH, to give a compoundhaving the formula B=NCH= r 1 wherein R is hydrogen and B=N is a memberof the group consisting of di lower alkylamino, 1 piperidyl,lower-alkylated l-piperidyl, 1 pyrrolidyl, lower-alkylated l pyrrolidyl,4-morpholinyl, lower-alkylated 4-morpholinyl, l-piperazinyl, and4-lower-alkyl-l-piperazinyl. Compounds of Formula IX where R islower-carboxylic acyl are obtained by esterifying the 17-hydroxycompounds with the appropriate acid halide or acid anhydride. Thecompounds of Formula IX are useful as hypotensive agents. Each member ofthe group defining N B has this activity.

3-hydroxymethyleneandrostan 17p ol-2-one is also a valuable intermediatein preparing heterocyclic substituted steroids having anabolicproperties. For example, it reacts with hydrazine to form17l3-hydroxyandrostano[2,3- c] pyrazole, and with hydroxylamine to forml76-hydroxyandrostano[2,3 c]isoxazole and the isomeric [3,2 d]isoxazole. The isomeric isoxazoles can be separated by making use of thefact that the [3,2,-d]isoxazole is readily cleaved by alkali to form thebase-soluble 3B-cyanoandrostan-175-ol-2one, whereas the [2,3-c1isoxazoleis stable to alkali. The 17fi-hydroxy group in the heterocyclic steroidscan be esterified by conventional esterification procedures.

The structures of the compounds of the invention were established by themodes of preparation, by chemical properties, by elementary analysis,and ultraviolet and infrared spectra.

The invention is illustrated by but not limited to the followingexamples.

EXAMPLE 1.Reaction of 2ot-bromo-17B-acetoxyandrostan-3one withn-propylmercaptan A mixture of g. (0.049 mole) of 2a-bromo-17B-acetoxyandrostan-3-one I, 15.2 g. (0.2 mole) of n-propylmercaptan and250 ml. of chloroform was refluxed under nitrogen for six hours. Thesolvent was removed at below 60 C. under 15 mm. pressure. The pressurewas then lowered to 0.08 mm., whereupon 5.6 g. of slightly impuredipropyl disulfide distilled, B.P. 37-40 C. (0.08 mm.) or 195196 C. (1atm.), n 1.4952. Its infrared spectrum was found to be identical withthat of an authentic sample.

The residual reaction mixture was then heated at 100 C. for one hourwith 50 m1. of pyridine and 25 ml. of acetic anhydride. Excess reagentswere removed by warmingin vacuo and the residual oil was dissolved inether. The solution was washed with 2 N sodium hydroxide, 2 Nhydrochloric acid and saturated salt solution, and was concentrated toan oily residue. The residue in 1:9 etherpentane was poured onto acolumn of 500 g. of silica gel. The column was eluted with 4 l. of thissame 1:9 mixture to give 13 g. of an oil which will be referred to belowas Mixture A. Further elution with 9 l. of the 1:9 solvent mixturefollowed by 13 l. of a 1:4 ether-pentane mixture afforded 5.5 g. ofcrystalline solid.

The 5.5 g. sample was dissolved in 50 ml. of hot methanol and thesolution was concentrated to a 20 ml. volume.

The solution was cooled to 6 C. and the precipitate of colorless plateswas collected (3.2 g.). This product was recrystallized from methanol togive 2.85 g. of 17B-acetoxyandrostan-Z-one (V, acetate), M.P. 148150 C.One further recrystallization raised the melting point to 149.2 150.0 C.(corn); [oc] =+26.8 (chloroform).

Immediately following the separation of the 3.2 g- Of Z-ketone above, aheavy precipitation of needles occurred in the filtrate. This solid wascollected (1.0 g.) and recrystallized twice from methanol to give 0.8 g.of 17B-acetoxyandrostan-Z-one dimethylketal, M.P. 142.5-1445" C.; [a]=5.2 (chloroform).

Mixture A, described above, was rechromatographed on 280 g. of neutralalumina. El ution of the column with 5% ether% pentane caused immediateremoval of 2.65 gof oily17,8-acetoxy-3,3-bis(n-propylmercapto)androstane (VIII, R is CH CH CH Ris COCH which solidified. One recrystallization from methanol gave 2.0g. of fine needles, M.P. 96.598 C. This melting point was undepressedupon admixture of the material with an authentic sample M.P. 96.598 C.prepared from l7fl-acetoxy-5utandrostan-3-one and n-propylmercaptan inthe presence of boron trifiuoride etherate, and the infrared spectra ofthe two samples were identical.

When dioxane was substituted for chloroform as the solvent similarresults were obtained. The reaction was also successful when then-propylmercaptan was replaced by equivalent amounts of methylmercaptan,isopropylmercaptan or isobutylmercaptan.

The starting 2ot-bromo-17fi-acetoxyandrostan-3-one can be replaced bythe free carbinol, 2a-bromoandrostan-17,8 o1-3-one, or by otherlower-carboxylic acid esters there of, e.g., the propionate, caproate,benzoate, pnitrobenzoate, flcyclohexylpropionate, hemisuccinate,cinnamate, and the like.

EXAMPLE 2.--Preparation of 17B-acetoxyandrostan-2- one under optimumconditions A mixture of 157.5 g. (0.384 mole) of17fi-acetoxy-2mbromoandrostan-3-one, 118.5 g. (1.55 moles) ofn-propylmercaptan and 1750 ml. of chloroform was refluxed in a nitrogenatmosphere for fourteen hours and then concentrated in vacuo to aresidual oil. This oil was dissolved in a mixture of 1 l. of methanol,50 ml. of concentrated hydrochloric acid and 50 ml. of water. Theresultant cloudy solution was refluxed with stirring for four hours.During this reflux period, 10 ml. portions of water were added everyfifteen minutes. Finally, 1.5 l. of water was added and the mixture wasdistilled under water pump vacuum. As the volume of the still potcontents diminished, 5% aqueous hydrochloric acid was added to maintainapproximately the original volume. After 8 l. of distillate had beencollected no further oily droplets could be observed co-di-stilling withthe water. The pot contents were cooled, and the solid material wascollected and dried.

The solid material was heated at 100 C. for one hour with 250 ml. ofacetic anhydride and 500 ml. of pyridine and the cooled mixture waspoured into 10 l. of cold water. The precipitated solid was collectedand air-dried.

A solution of the solid reaction product in 3 l. of boiling methanol wastreated with a solution of 450 g. of sodium metabisulfite in 2.2 l. ofwater at 25 C. This mixture was stirred for fifteen minutes and thendiluted with 2.5 l. of methylene dichloride and 2.5 l. of water.Stirring was continued for fifteen minutes. The mixture was filtered,the layers of the filtrate were separated and the water layer and thesolid were set aside. The organic layer was dried over sodium sulfateand concentrated to a solid residue. This residue was dissolved in 250ml. of acetone and 250 ml. of hexane, the solution was decolorized withactivated charcoal and filtered, and the filtrate was concentrated to a100 ml. volume. Cooling afforded 50 g. of 17(3-acetoxyandrostan-2-one,M.P. 147-150 C. Further recrystallization of the product 7 and reworkingof the mother liquors gave a 41.5% total yield of material melting at15015l C.

The water layer and the solid which were set aside in the bisulfiteseparation just described were combined, treated with 4 l. of methylenedichloride and 500 g. of sodium bicarbonate and heated for five hoursunder reflux. The mixture was cooled, filtered, and the methylenedichloride layer of the filtrate was dried over sodium sulfate. Thissolution was concentrated to a residual solid which was heated for onehour at 100 C. with 50 ml. of acetic anhydride and 100 ml. of pyridine.Cooling of the reaction mixture and dilution with 3 l. of cold watergave a solid which was recrystallized once from ethyl acetate. The17fl-acetoxy-5a-androtsan-3-one so obtained (62 g., 49% yield) melted atl56159 C. Its identity was confirmed by infrared spectral comparisonwith an authentic sample.

The foregoing procedure can be applied to other cbromo-3-oxo-steroids ofthe A/ B trans configuration bearing substituents inert under theconditions of the process. For example, cholestan-Z-one was preparedfrom 2abromocholestan-S-one as follows:

EXAMPLE 3 A solution of 6.96 g. (0.0145 mole) of 2a-bromocholestan-3-oneand 4.40 g. (0.058 mole) of n-propylmercaptan in 150 ml. of chloroformwas refluxed for seven hours and then concentrated in vacuo to removethe volatile solvent. The residual oil was dissolved in 250 ml. of 1:9etherpentane and poured onto a column of 250 g. of silica gel. Elutionof the column with 1 liter of the same solvent mixture afforded 5 .64 g.of an oily mixture. Further elution of the column brought outcrystalline material which when recrytsallized from acetone gave 1.45 g.of cholestan-2-one in the form of colorless blades, M.P. 128-130" C.,[a] =+49.4 (1% in chloroform).

EXAMPLE 4.-17 B-hydroxyandrostan-2-one V 17;?-acetoxyandrostan-Z-one(1.76 g., 0.0053 mole) was treated with 1.05 g. (0.16 mole) of 85%potassium hydroxide pellets in 75 ml. of 95% ethanol at boilingtemperature for ninety minutes. Acetic acid (2 ml.) was added and thevolatile solvent was removed by warming in vacuo. The solid residue waspartitioned between water and ether. The ether layer was separated,washed with saturated salt solution, dried over sodium sulfate andconcentrated to dryness. Recrystallization of the residue from ethylacetate gave 1.43 g. of 17B-hydroxyandrostan-2-one in the form ofcolorless blades, M.P. 178.0-l80.0 C. (corr.); [a] =+47.6 (chloroform).

17,8-acetoxyandrostan-Z-one dimethylketal (0.40 g.) was refluxed for twohours in aqueous alcoholic sodium hydroxide solution and the solutionwas concentrated in vacuo until all alcohol was removed. Water was addedto the residual suspension and the solid present was collected. It wasrecrystallized twice from methanol to give 0.18 g. of17fi-hydroxyandrostan-2-one dimethylketal in the form of colorlesstablets, M.P. 185-1875 C.,

2.92, 6.85 and 6.94 [a] =-]ll.l (chloroform) EXAMPLE 5.-173-acetoxyandrostan-Z-one oxime A solution of 7.00 g. (0.021 mole) of17B-acetoxyandrostan-Z-one and 7.00 g. (0.10 mole) of hydroxylaminehydrochloride in 175 ml. of absolute ethanol was refluxed for eighteenhours and concentrated to a residue in vacuo. The residue waspartitioned between water and methylene dichloride, the layers wereseparated and the organic layer was washed with 2 N hydrochloric acidand dried over sodium sulfate, and then concentrated to dryness. Thisresidue was dissolved in 2:1:7 methylene dichloride-ether-pentane, andthis solution was poured onto a 250 g. column of silica gel. Elutionwith 1:9 etherpentane gradually changed to 4:6 ether-pentane brought out6.06 g. of oxime which was recrystallized from ethyl 8 acetate to give4.53 g. of 17,8-acetoxyandrostan-Z-one oxime of M.P. 204.6209.6 C.(corr.), [a] =63.1 (chloroform).

17,8-acetoxyandrostan-Z-one oxime was found to possess antihypertensiveactivity when administered to renal hypertensive rats at a dose level of100 mg./kg.

The acetate of 17,8-acetoxyandrostan-2-one oxime was prepared asfollows. A solution of 2.69 g. of 17fl-acetoxyandrostan-Z-one oxime in10 ml. of acetic anhydride and 20 ml. of pyridine was heated on thesteam bath for one hour, cooled and poured into 300 ml. of water. Theprecipitated solid was collected and recrystallized once from methanolto give 1.27 g., M.P. 161166 C. A second recrystallization from methanolafforded a sample having the M.P. 167.8170.0 C. (corr.), [a] =61.0(chloroform).

A solution of 4.0 g. (0.014 mole) of 17,8-hydroxy-5aandrostan-Z-one in50 ml. of tetrahydrofuran and 50 ml. of ether was treated dropwise withstirring with 30 ml. of 3 M methyl-magnesium bromide (0.09 mole). Themixture was refluxed with stirring for two hours, cooled and treatedwith 30 ml. of saturated aqueous ammonium chloride. The layers wereseparated, the water layer was extracted with ether and the combinedeither solutions were concentrated to dryness. This residue wasdissolved in 100 ml. of methylene dichloride, and the solution wasdiluted with 50 ml. of ether and 350 ml. of pentane, and then pouredonto 200 g. of silica gel. Elution with 3:7 etherpentane afforded 2.6 g.of the desired diol which was recrystallized twice from methanol to give2.1 g. of 2amethlandrostane 25,175 diol, M.P. 193.2 197.2 C. (corr.),[a] =-+16.0 (1% in EtOH).

EXAMPLE 7.2ot-methylandrostan-2fi-ol-17-one A solution of 1.10 g.(0.0036 mole) of Zm-methyI-Saandrostane-2fi-17,8-diol in 50 ml. ofacetic acid was cooled to 16 C. and treated with 0.39 g. (0.0039 mole)of chromium trioxide in 1 ml. of water and 25 ml. of acetic aciddropwise with stirring at 1620 C. during thirty minutes. The mixture wasstirred for three hours, diluted with 500 ml. of water, and theprecipitated solid was collected and air-dried. This solid (1.0 g.) wasdissolved in 20 ml. of methylene dichloride, 40 ml. of ether and 55 ml.of pentame and the solution was percolated through 25 g. of silica gel,the column having been washed with 2:3 etherpentane. Concentration ofthe first 600 ml. of eluate and recrystallization of the residue frommethanol afforded 0.80 g. of 2a-me'thylandrostan-2 8-ol-17one, M.P. 197-201 C. A second recrystallization from methanol gave 0.65 g. ofcolorless, massive prisms, M.P. 199.2-202.5 C. (corr.), [oc] ='+9l.4 (1%in chloroform).

EXAMPLE 8 2a,17ot-dimethylandrostane-ZB,175-diol was prepared from 2.93g. (0.0096 mole) of 2a-methyl-5lx-androstan- 2 3-ol-17-one in ml. oftetrahydrofuran and 15 ml. of 3 M methylmagnesium bromide (0.045 mole)according to the procedure described above in Example 6. The product wasrecrystallized from acetone to give2a,17u-dimethylandrostane-2B,17fl-diol, M.P. 186.8194.8 C. (corr.), [u]=-2.1 (1% in chloroform).

EXAMPLE 9.17fi-acetoxy-2-n-pr0pylmercaptoandrostan-3-one (II; R is CH CHCH R is COCH A mixture of 16.4 g. (0.040 mole) of 2a-bromo-17 3-acetoxyandrostan-3-one (I) and 3.34 g. (0.044 mole) of n-propylmercaptanin 250 ml. of dry t-butyl alcohol was refluxed for five and one-halfhours, and then concentrated to remove the volatile solvent by warmingin vacuo. The residual oil was diluted with 25 ml. of ether and 475 ml.of pentane and poured onto 300 g. of silica gel. The first 25 l. ofeluate contained negligible material and the respectively,

first solid subsequently eluted was mushy and was discarded (less than 1g.). The desired product was then collected and recrystallized threetimes from methanol to give 4.55 g. of17,6-acetoxy-Z-n-propylmercaptoandrostan- 3-one in the form ofcolorless, massive prisms, M.P. 116- 118.5 C., and a second crop of 1.04g., M.P. 113- 117 C.

By replacing the 2ot-bromo-17fi-acetoxyandrostan-3-one in the foregoingpreparation by a molar equivalent amount of2a-bromoandrostan-l7fl-ol-3-one,2ot-bromo-l7fi-benzoyloxyandrostan-B-one orZa-bromo-17fl-cinnarrnoyloxyandrostan3-one, there can be obtained,respectively, 2-npropylmercaptoandrostan 17B ol 3 one (II; R is CH CH CHR is H), 175-henzoyloxy-2-n-propylmercaptoandrostan-B-one (II; R is CHCH CH R is COC H or 17fi-cinnamoyloxy-Z-n-propylmercaptoandrostan-3-one(II; R is CH CH CH R is COCH: CHC H By replacing the n-propylmercaptanin the foregoing preparation by a molar equivalent amount ofmethylmercaptan or n-hexylmercaptan, there can be obtained,respectively, 17/3-acetoxy-2-methylmercaptoandrostan-3-one (I I; R is CHR is COCH or 17B-acetoxy-2-n-hexylmercaptoandrostan-3-0ne (II; R is CH(CH R is COCH EXAMPLE 10.l7,8-acetoxy-2,3 -bis (n-propylmercapto2-androstene (III; R is CH CH CH R is COCH A mixture of 16.0 g. (0.039mole) of 2ot-bromo-17,B- acetoxyandrostan-B-one and 12.2 g. (0.16 mole)of npropylmercaptan in 350 ml. of dry t-butyl alcohol was refluxed forfive and one-half hours, and then concentrated to remove volatilesolvent by warming in vacuo. The residual oil was diluted with 25 ml. ofether and 475 ml. of pentane and poured onto a silica gel column (500g.). Elution of the column with 2 l. of 1:19 ether-pentane removeddi-n-propyl disulfide (0.36 g.) and the same solvent mixture removed thedesired product which was recrystallized from 11 ml. of absolute ethanolto give a 8.7 g. of 17/8-acetoxy-2,3-bis(n-propylmercapto)-2-androstenein the form of long, colorless prisms, M.P. 48-54 C. Two furtherrecrystallizations altorded 7.35 g. of material melting at 50-53.5 C.,[a] =+58.8 (chlorofOrrn), 6221 and 6253 Further elution of the columnwith the same solvent afiorded17fl-acetoxy-2-n-propylmercaptoandrostan-3-one (II; R is CH CH CH R isCOCH which was recrystallized four times from methanol to give 1.35 g.of massive prisms, M.P. 1168-1196 C. (corr.), [u] =+66.0 (chloroform),6243 320 and 6 250.

By replacing the 2a-bromo-l7;8-acetoxyan drostan-3-one in the foregoingpreparation by a molar equivalent amount ofZu-bromO-androstan-17B-ol-3-one, Zu-brorno-17fl-benzoyloxyandrostan-3-one or2u-bromo-l7fi-cinnamoyloxyandrostan-3-one, there can be obtained,respectively, I 2,3-bis(n-propylmercapto)-2-androsten-17;3-ol III; R isCH CH CH R is. H), 17fi-benzoyloxy-2,3-bis(npropylmercapto)-2-androstene(III; R is CH CH CH R is COC H or17fi-cinnamoyloxy-2,3-bis(n-propylmercapto)-2-androstene (III; R is CHCH CH R is COCH=CHC H By replacing the n-propylmercaptan in theforegoing preparation by a molar equivalent amount of methylmercaptan orn-hexylmercaptan, there can be obtained,

17;8-acetoxy-2,3-bis(methylmercapto)-2-androstene (III; R is CH R isCOCH or 17/3-acetoxy-2,3- bis(n-hexylmercapto)-2-androstene (III; R isCH (CH R is COCH Desulfurization of.17,6-acetoxy-2-n-propyllmercaptoandrostan-3-one and17e-acetoxy-2,3-bis(n-propylmercapto)-2-androstene with Raney nickelgave, respectively, l7B-acetoxyandrostan-3-one. M.P. 158.5-160" C., and17B-acetoxy-2-androstene, M.P. 92.595 C., identical with authenticsamples of these known compounds.

EXAMPLE 1 1.17,8-acetoxy-3n-propylmercapto-2- androstene (VI; R is CH CHCH R is COCH A solution of 9.58 g. of17/3-acetoxy--3,3-bis(n-propylmercapto)androstan-3-one (Example 1) and0.3 g. of ptoluenesulfonic acid monohydrate in 100 ml. of benzene wasboiled slowly for four hours. Fresh benzene was added occasionally tomaintain the volume. The solvent was then removed by warming in vacuo,the residual oil was dissolved in ether and this solution was washedwith dilute sodium. hydroxide solution and dried over sodium sulfate.Removal of solvent gave a pasty solid which was triturated with one5-ml. portion and three Zarnl. portions of methanol containing a traceof pyridine. The resulting powdery solid was recrystallized from 45 ml.of methanol to give 1.7 g. of17B-acetoxy-3-n-propylmercapto-Z-androstene. A single furtherrecrystallization gave a sample of the M.P. 75.4-76.2 C. (corr.), [u]=+60.6 (chloroform), 5223 and E238 243 my17/i-acetoxy-3-n-propylmercapto-2-androstene can be hydrolyzed to3-n-propylmercapto-Z-androsten17,8-01 (VI; R is CH CH CH R is H) bywarming it with a methanolic solution of potassium hydroxide.

EXAMPLE 1 2.-l 7 [1-acetoxy-2-n-propylmercapto-2- androstene (IV; R isCH CH CH R" is COCH A solution of 2.0 g. of 17/3-acetoxyandrostan-2oneand 2.0 g. of n-propylmercaptan in 30 ml. of benzene was treated with 4drops of boron trifluoride ethereate and allowed to stand for two days.Water droplets separated from the solution. The mixture wasconcentratedto a residue by warming below 35 C. in vacuo, the residuewas dissolved in ether and this solution was washed with 2 N sodiumhydroxide solution, and then dried over sodium sulfate. Concentration ofthe ether solution gave an oil which was dissolved in 10 ml. of pentane.A solid precipitated which was collected and washed with two S-ml.portions of cold pentane. This solid, 0.87 g., melted at l48.5150 C. andconsisted of starting material.

The filtrate was concentrated to a residual oil which solidified whenchilled. This solid was slurried with 5 ml. of cold methanol containinga trace of pyridine and the solid was collected. It was thencrystallized from 10 ml. of methanol containing a drop of pyridine togive 05 8 g. of colorless needles of l-acetoxy-2-n--propylmercapto-2-androstene, M.P. 59-60.5 C. A second recrystallization from the samesolvent gave material which melted at 60.5-62 C., resolidified, and thenmelted at 70.0-70.5 0; [a] =+52.2 (chloroform), 6 4200, 235443 m 3100'By repacing the n-propylmercaptan in the foregoing preparation by amolar equivalent amount of methylmercaptan or n-hexylmercaptan, therecan be obtained, respectively, 17fi-acetoxy-2methylmercapto-2-androstene(IV; R is CH R is COCH or l7fl-acet-oxy-2-n-hexyl mercapto-Z-androstene(IV; R is CH (CH R is COCH By replacing the 17B-acetoxyandrostan 2 onein the foregoing preparation by a molar equivalent amount ofandrostan-17,B-ol-2-one, there can be obtained2-n-propylmercapto-Z-androsten-17fi-ol (IV; R is CH CH CH R is H).

EXAMPLE 13.17,B-acetoxy-2,3-bis(n-propanesulfonyl -2-androstene Asolution of 3.0 g. (0.0065 mole) of 17/3-acetoxy-2,3-bis(n-propylmercapto)-2-androstene (Example 10) in 15 ml. of acetic acidwas treated with 6 g. (0.5 mole) of 30% hydrogen peroxide in 1 g.portions. The temperature rose spontaneously to 46 C., then dropped.This solution was heated at 60 C. for nineteen hours, cooled and pouredinto water. The solid which precipitated was collected, airdried andrecrystallized from methanol to give 2.85 g. of colorless needles, M.P.140.5-l44.5 C. Chromaotgraphy of this solid on g. of silica gel usingether-pentane mixtures (finally 3:7) for elution afforded 17eacetoxy 2,3bis(n-propanesulfonyl)-2-androstene which was recrystallized frommethanol to give 1.97 g. of needles, M.P. 147.4-148.8 C. (corr.), [a]=+82.8 (chloroform), 6 my 9300.

17;? -acetoxy-2,3-bis(n-propanesulfonyl)-2-androstene can be hydrolyzedby warming with a methanolic solution of potassium hydroxide to give 2,3-bis(n-propanesulfonyl)-2-androstene-l7 3-ol.

EXAMPLE 14.-17fl-acetoxy-3 -n-propanesulfonyl- 2-androstene A stirredsolution of 4.2 g. (0.011 mole) of17fl-acetoxy-3-npropylmercapto-2-androstene (Example 11) in 50 ml. ofether at 30 C. was treated with 93 ml. (0.051 mole) of an etherealsolution of monoperphthalic acid which contained 100 mg. of peracid perml. of solution. The resulting solution was allowed to warm to roomtemperature and stand for six days, was filtered, and the filtrate waswashed with sodium carbonate, dried over sodium sulfate and concentratedto a residual oil which solidified. Two recrystallizations from methanolafforded 2.68 g. of colorless needles, M.P. 120129 C. The product wasrecrystallized twice more from methanol with drying at 78/1 mm. foreight hours to give 17;?- acetoxy-3-n-propanesulfonyl 2 androstene, M.P.126.0- 129.2 C. (corr.); [a] =+45.4 (chloroform).

17;? acetoxy-3-n-propanesulfonyl-2-androstene can be hydrolyzed bywarming with a methanolic solution of potassium hydroxide to give3-n-propanesulfonyl-Z-androsten-17,B-ol.

EXAMPLE 15 l7fl-acetoxy-2-n-propanesulfonyl-2-androstene was preparedfrom 17B-acetoxy-2-n-propylmercapto-2-androstene (2.7 g., 0.0069 mole)and 0.035 mole of ethereal perphthalic acid in the manner describedabove in Example 14. The product was recrystallized twice from methanolto give 1.15 g. of 17,8-acetoxy-2-n-propanesulfonyl-Z-androstene, M.P.185.0186.0 C. (corr.), [a] =+45.4 (chloroform).

17;? acetoxy-2-npropanesulfonyl-2-androstene can be hydrolyzed bywarming with a methanolic solution of potassium hydroxide to give3-n-propanesulfonyl-2-androsten-17fi-ol.

EXAMPLE 16 l7,8-acetoxy-3,3-bis(n-propanesulfonyl)androstane wasprepared from 5.0 g. (0.011 mole) of 17B-acetoxy-3,3-bis(n-propylmercapto) -androstane (Example 1) and 0.10 mole of etherealmonoperphthalic acid in the manner described above in Example 14. Theproduct was recrystallized from methanol to give 17fl-acetoxy-3,3-bis(npropanesulfonyl)androstane in the form of colorless needles, M.P.137.2139.0 C. (corr.); [a] =+14.O (chloroform).

l7fl-acetoxy-3,3-bis(n-propanesulfonyl)androstane can be hydrolyzed bywarming with a methanolic solution of potassium hydroxide to give3,3-bis(n-propanesulfonyl)androstan-17;3-ol.

l7fl-acetoxy-3,3-bis(n-propanesulfonyl)androstane was found to possessanti-pituitary and anti-cortical activity.

3,3-bis(n-propanesulfonyl)androstan-l7,B-ol can be oxidized with chromicacid to give 3,3-bis(propanesulfonyl)- androstan-l7-one, prisms, M.P.145.4148.8 C. (corr.).

EXAMPLE 17.3-hydroxymethyleneandrostan- 17B-ol-2-one Sodium methoxidewas freshly prepared by dissolving 0.70 g. (0.029 mole) of sodiumhydride in ml. of methanol and removing all excess methanol by warmingin vacuo. Pyridine (37 ml.) was added followed by 1.95 g. (0.0067 mole)of androstan-l7 8-ol-2-one and 4 ml. of ethyl formate. This mixture wasallowed to stand at room temperature for eighteen hours and thenconcentrated to a residue by warming in vacu-o. The residue waspartitioned between water and ether, and the water layer was separatedand treated with carbon dioxide until the pH of the solution fell to7.5. Extraction with ether separated the product which was thenrecrystallized twice from acetonitrile to give3-hydroxymethyleneandrostan-175-01- 2-0ne in the form of colorlessmassive prisms, M.P. 141.2- 142.4 C. (corr.) (evacuated capillary), [a]=+47.4 (chloroform); 6 m 9000.

EXAMPLE 18.-3-diethylaminomethyleneandrostan-17B- ol-2-one [IX; B=N is(C H N, R' is H] A mixture of 2.0 g. (0.0063 mole) of3-hydroxymethyleneandrostan-17,8-ol-2-one (Example 17), 50 m1. ofbenzene and 3 ml. of diethylamine was refluxed for two hours with aWater separator attached to the system. Concentration of the reactionmixture by warming in vacuo afforded a residue which was recrystallizedonce from acetonitrile to give 1.80 g. of pale yellow needles, M.P.229236 C. A second recrystallization afforded 1.56 g. of material whichmelted at 229-237" C. (immersed at 200 C. and heated at 3 /min.). Thismelting point varied with rate of heating and temperature of immersionof the sample. The product showed [u] =65.7 (chloroform) and 6 22,600.

By replacement of the diethylamine in the foregoing preparation by amolar equivalent amount of di-n-hexylamine, pyrrolidine, piperidine,morpholine, piperazine, 3-methylpyrrolidine, 4-ethylpiperidine,2-methylmorpholine or 4-methylpiperazine, there can be obtained,respectively, 3 (di n hexylamino)methyleneandrostan- 17,8-01-2-one [IX;B N is (nC H N, R is H], 3- (l pyrrolidyl)methyleneandrostan 17B ol2-one [IX; B N is l-pyrrolidyl, R is H],3-(1-piperidyl)-methyleneandrostan-17B-ol-2-one [IX; B N is 1-piperidyl,R is H], 3 (4-m-orpholinyl)methyleneandrostan-l7B-ol-2-one [IX; B=N is4-morpholinyl, R is H],3-(1-piperazinyl)methyleneandrostan-17fi-ol-2-one [IX; B N isl-piperazinyl, R is H],3-(3-methy-l-pyrrolidyl)methyleneandrostan-l7fiol-2-one, 3-(4-ethyll-piperidyl methyleneandrostan- 171 ol-2-one, 3-(2-methyl-4-morpholinyl methyleneandrostan- 17/8-ol-2-one, or3-(4-methyl-1-piperazinyl)methyleneandrostan-l7B-ol-2-one.

3-diethylaminomethyleneandrostan-17fl-ol-3-one can be caused to reactwith acetic anhydride, caproyl chloride, succinic anhydride,fi-cyclopentylpropionic anhydride, benzoyl chloride, p-nitrobenzoylchloride or cinnamoyl chloride, in the presence of pyridine, to give,respectively, the 17-acetate, 17-caproate, 17-hemisuccinate, l7-( 3-cyclopentylpropionate), 17-benzoate, 17-(p-nitrobenzoate) or17-cinnamate of 3-diethylaminomethyleneandrostan-17fl-ol-2-one.

EXAMPLE 19.17/3-hydroxyandrostano[2,3-c] pyrazole A mixture of 2.00 g.(0.0063 mole) of 3-hydroxymethyleneandrostan-17,8-ol-2-one (Example 17),2 g. of hydrazine hydrate and 25 ml. of absolute ethanol was heatedunder reflux for thirty minutes, cooled and diluted with 100 -ml. ofwater. The white solid which separated was collected, air-dried andrecrystallized twice from acetone to give 1.60 g. of l78-hydroxyandrostano [2,3-c]pyrazole containing a half molecule ofacetone of crystallization, colorless prisms, M.P. 233-234" C. (corr.),[u] :+S0.3 (1% in EtOH), 6 5,200.

l7t3-hydroxyandrostano[2,3-c]pyrazole can be caused to react with aceticanhydride or fl-cyclopentylpropionic anhydride in the presence ofpyridine to give the 17-acetate or 17- ,B-cyclopentylpropionaterespectively. EXAMPLE 20.-17fi-acetoxyandrostanol[2,3-c]isoxazole Amixture of 3.28 g. (0.040 mole) of fused sodium acetate, 2.92 g. (0.042mole) of hydroxylamine hydrochloride, 8.60 g. (0.027 mole) of3-hydroxymethyleneandrostan-l7/3-ol-2-one (Example 17) and 270 ml. ofacetic acid was warmed at 65-70 C. with stirring for six hours, and thenconcentrated by warming in vacuo. The residue was partitioned betweenwater and ether, the layers were separated, and the ether layer waswashed with saturated sodium bicarbonate solution, dried over sodiumsulfate and concentrated.

The 10.68 g. residue present at this point was a mixture of17fi-hydroxyandrostano[2,3-c]isoxazole and17,6-hydroxyandrostano[3,2-d]isoxazole. The mixture was dissolved in 330ml. of tetrahydrofuran, 2.65 g. (0.049 mole) of sodium methoxide wasadded and the mixture waseallowed to stand for ninety minutes. Themixture was concentrated in vacuo, Water and ether were added, thelayers were separated, and the ether layer was washed with 2N sodiumhydroxide, dried over sodium sulfate and concentrated. Recrystalliaztionof the residue from methanol afforded 5.0 g. ofl7p-hydroxyan-drostano[2,3- c]isoxazole, M.P. l7 4-l78 C. aftershrinking at about 169 C. This product was found to contain methanol ofsolvation which was difficult to remove entirely so the compound wasconverted to its acetate by means of acetic anhydride and pyridine usinga one-hour heating period followed by dilution with water.Recrystallization from 'methanol and drying for six hours at 100/ 10 mm.

afforded 4.37 g. of 17/3-acetoxyandrostano[2,3-c]isoxazole, M.P.177.4-178.2 C. (corn), [011 +39.2 (1% in chloroform) The water layerfrom the reaction of the isoxazole mixture with sodium methoxide intetrahydrofuran was treated with carbon dioxide until the pH of themixture 1. The process for preparing a 2-oxo-steroid having the A/Btrans configuration which comprises heating a 2a-bromo-3-oxo-steroidhaving the A/ B trans configuration with at least about three molarequivalents of a lower-alkylmercaptan, and hydrolyzing the product inthe presence of dilute acid.

2. The process for preparing androstan-17fl-ol-2-one which comprisesheating a member of the group consisting of2a-bromoandrostan-17B-ol-3-one and lower-carboxylic acid estersthereofwith at least about three molar equivalents of alower-alkylmercaptan, and hydrolyzing the product in the presence ofdilute acid.

3. Androstan-17fiol-2-one.

4. 17/3-acetoxyandrostan-Z-one.

5. 17,3-acetoxyandrostan-Z-one oxime.

6. 17fl-acetoxyandrostan-Z-one oxime acetate.

7. 2a-methylandrostane-2 3,17/3-diol.

8. 2a-methylandrostan-Zfi-ol-17-one.

9. 2a,17a-dimethyIandrOstane-ZB,17fl-diol.

10. A compound of the formula R CH2 wherein R is lower-alkyl and R is amember of the group consisting of hydrogen and lower-carboxylic acyl.

wherein R is lawer-alkyl and R is a member of the group consisting ofhydrogen and lower-carboxylic acyl.

12. A'compound of the formula CH3 CH3 0 RSO2 wherein R is lower-alkyland R is a member of the group consisting of hydrogen andlower-carboxylic acyl.

13. A compound of the formula wherein R is lower-alkyl and R is a memberof the group consisting of hydrogen and lower-carboxylic :acyl.

14. A compound of the formula OR CH3 wherein R is lower-alkyl and R is amember of the group consisting of hydrogen and lower-carboxylic acyl.

15. A compound of the formula O R CH3 wherein R is lower-alkyl and R isa member of the group consisting of hydrogen and lower-carboxylic acyl.

16. A compound of the formula wherein R is lower-alkyl and R is .amember of the group consisting of hydrogen and lower-carboxylic acyl.

17. A compound of the formula wherein R is lower-alkyl and R is a memberof the group consisting of hydrogen and lower-carboxylic acyl.

18. 3,3 -Bis (n-propanesulfonyl andr0stan-17-one.

19. 3-Hydroxymethyleneandrostan-17fl-ol-2-one.

20. A compound of the formula CIIg O R CH? B=NCH= wherein R is selectedfrom the group consisting of hydrogen and a hydrocarbon carboxylic acylgroup of less than 12 carbon atoms; R is hydrogen; R and R are loweralkyl; and R and R together with the nitrogen atom form a heterocyclicradical selected from the group consisting of piperidino, morpholino andpyrrolidino.

24. 3-N,N-diethylaminomethylene androstan 17pol-2-one.

25. Isoxazolo(5,4';2,3)-androstan-17fi-ol.

References Cited UNITED STATES PATENTS 3,280,113 10/ 1966 Christiansenet a1.

HENRY A. FRENCH, Primary Examiner.

US. Cl. X.R.

257 :93 UM'JISD s'l'iifnas PA'HCIIT omen CE FHjFICAiIEJ OF CORRECTIQNPatent N 3, 415,816 Dated December 10, 1968 Invent r) Robert L. ClarkeIt is certified that error appears in the above-identified patent andthat said Letters PaLont are hereby corrected as shown below:

r Column 1, line 1?, "process of aspect" should read I --processaspect--. Column '4, line 55, "or the preparation" should read -for thepre aration--; line 56, "aspects" should read --aspect--. Column line26, "either" should read --ether-. Column 12, line t}, "-j-one" shouldread -2-one-; line 69, "-acetoxyandrostanol" should read-acetoxyandrostano-. Column 13, lines 60-70, Claim 10, left-hand portionof formula,

CH CH H H should read Column 1 line 14, Claim 11, "lawer" should read--1ower--. Column 15, lines 15-25, Claim 17, left-hand portion offormula,

H II

should read R-SO R-SO R- so 2 ii Column 16, line 1 1, Claim 22,"cyanondrostan" should read --cyanoandrostan-.

SiGJlED PM. SEALED AUG18197U J (SEAL) Anew Edward M. Fletcher, Ir.

Attesting Officer

3. ANDROSTAN-17B-OL-2-ONE.
 20. A COMPOUND OF THE FORMULA